The overall goal of this Program Project is to improve the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in the treatment of hematological malignancies. We hope to achieve this goal by developing methods to improve the safety of the procedure, to increase its ability to eradicate malignancy, and to expand the application of transplantation to a broader population. Eight individual projects are proposed: 1. Nonmyeloablative Hematopoietic Stem Cell Allotransplants 2. Overcoming Genetic Barriers in Hematopoietic Stem Cell Transplantation 3. Induction of Immunological Tolerance after Hematopoietic Stem Cell Grafts 4. Pathophysiology and Prevention of Multi-organ Failure 5. Infectious Complications 6. Discovery and Validation of Genetic Markers of Prognosis and Residual Disease 7. Specific Adoptive Immunotherapy of Malignant Diseases 8. Minor Histocompatibility Antigens in Graft versus Leukemia Responses In addition, core support is requested in biostatistics, pathology, microbiology and virology, pharmacology, gastroenterology and pulmonary medicine, stem cell processing and storage, long-term follow-up, and administration. Our ability to successfully carry out the proposed work is greatly benefitted by: (1) the creation of a large group of investigators all focused on the general subject of HSCT; (2) the existence of strong preclinical research programs at our center in support of this topic; and (3) the accrual of 450-550 transplant patients onto research studies each year. Success in the achievement of our goal will not only benefit patients with hematological malignancies, but likely will have relevance for the use of intensive and immune based therapies to treat other malignant and nonmalignant diseases and for the care of the immunocompromised patient.